Different viruses elicit distinct phenotypes of memory cytotoxic T lymphocytes (CTL). This is reflected in differential expression of homing receptors and costimulatory molecules like CD27. Memory CTL retained CD27 following lymphocytic choriomeningitis virus (LCMV) infection, but not after immunization with recombinant vaccinia virus or tumor cells expressing LCMV glycoprotein. Stable CD27 expression on memory CTL required ligation by CD70 expressed on polyclonally activated B cells during the contraction phase. The functional consequence of CD27 expressed on virus-specific CTL was analyzed in CD27-deficient mice. LCMV infection of CD27 -/-mice revealed that primary CTL activation and expansion as well as elimination of the virus were independent of CD27 expression. In contrast, ligation of CD27 on memory CTL upon secondary antigen encounter increased clonal expansion and improved protection against re-infection. This points to novel B cell-CTL interactions during viral infection and to a beneficial role of polyclonal B cell activation that represents a characteristic of murine LCMV, human immunodeficiency virus and human hepatitis B and C virus infection.

IntroductionImatinib mesylate (STI571, Glivec; Novartis Pharma AG, Basel, Switzerland) selectively inhibits the tyrosine kinases (TKs) ABL, BCR/ABL, ARG, PDGF-R ␣ and ␤, and c-KIT. Constitutive activation of these TKs has been documented in chronic myeloid leukemia (CML), Philadelphia chromosome-positive (Ph ϩ ) acute lymphocytic leukemia, myeloproliferative disorders due to chromosomal rearrangements in PDGF-R, and gastrointestinal stromal tumors with mutations in c-KIT. [1][2][3][4] In these diseases, blocking of TKs with imatinib is very efficient and substantially improves clinical outcome.Since TKs are involved in various intracellular signaling pathways, it is not surprising that imatinib treatment affects immune responses. Clinical observations have suggested that imatinib treatment correlates with a reversible dose-dependent lymphopenia and hypogammaglobulinemia. 5 Experimental in vitro studies have demonstrated that imatinib inhibited the development of human CD34 ϩ progenitor cell-derived dendritic cells (DCs). In addition, DCs exposed to imatinib were less potent in inducing cytotoxic T-cell (CTL) responses against tumor and recall antigens. 6 However, results of the effect of imatinib on DC maturation are controversial. Other experiments have suggested a normal maturation but reduced expansion of DCs in mice when stimulated with Flt3L. 7 Further, it has been shown that treating DCs in vitro with imatinib enhanced antigen-presenting cell function and overcame tumor-induced CD4 ϩ T-cell tolerance. 8 In addition, several in vitro studies using T cells isolated from human peripheral blood have demonstrated a dose-dependent reduction of T-cell proliferation in the presence of imatinib. 1,9,10 These results raise the possibility that imatinib could affect normal immune functions through TK inhibition. TKs play a prominent role in T-cell receptor (TCR) and B-cell receptor (BCR) signal transduction, and, thus, it is conceivable that imatinib may interfere with this process. TCR ligation triggers a signaling cascade that includes activation of the TKs Lck, ZAP70, and Ltk. A recent study has reported the requirement of c-ABL and ARG TKs for TCR-dependent transcriptional activation. 11 c-ABL is activated by Lck and then leads to the phosphorylation of ZAP70. It remains unclear whether c-ABL activates only ZAP70 or also activates other downstream proteins. 12 However, primary T cells lacking functional ABL TKs showed decreased IL-2 production and cell proliferation in response to TCR stimulation. 11 Comparably, it has been shown that ABL phosphorylates the BCR coreceptor CD19, suggesting a role for ABL in the regulation of B-cell proliferation. 13 Taken together, these experiments suggest that imatinib treatment in vivo may crucially influence antiviral CD8 ϩ T-and B-cell responses. However, physiologic consequences of imatinib treatment on protective immune response have not yet been demonstrated.Primary infection with lymphocytic choriomeningitis virus (LCMV), a noncytopathic RNA virus, is controlled almost ex...

Chronic myelogenous leukemia (CML) is IntroductionChronic myelogenous leukemia (CML) is a malignant clonal myeloproliferative disease. The BCR/ABL fusion protein results from the reciprocal chromosomal translocation t(9;22) forming the Philadelphia chromosome (Ph). BCR/ABL is responsible for the malignant phenotype of leukemic cells in CML and increases cell proliferation, inhibits apoptotic processes, and alters cellular adhesion of myeloid cells. 1,2 CML is characterized by an initial chronic phase with a massive expansion of all stages of the granulocyte cell lineage. Eventually, hematopoietic differentiation becomes arrested and CML progresses to blast crisis with immature blast cells accumulating in the periphery. 1 Several studies have shown that cytotoxic T lymphocytes (CTLs) are involved in the immunosurveillance of CML. BCR/ ABL is a leukemia-specific antigen, and CTLs specific for peptides derived from its sequence could recognize CML cells in vitro and in vivo. 3,4 This suggests that there is efficient intracellular processing and presentation of BCR/ABL-derived peptides by CML cells. In addition, overexpressed self-proteins, such as proteinase-3, Wilms tumor 1 protein, and minor histocompatibility antigens, can act as leukemia-specific antigens for T cells. 5 Dendritic cells (DCs) are professional antigen-presenting cells and are key mediators for the initiation and regulation of both innate and adaptive immune responses. 6 DCs are a heterogeneous population that can be divided into myeloid and plasmacytoid DCs based on their origin, expression of surface markers, and function. 7 As CML mainly affects cells of the myeloid lineage, it is probable that myeloid BCR/ABL-expressing DCs are circulating in CML patients. Indeed, BCR/ABL-expressing DCs could be detected in the peripheral blood of CML patients. 7,8 However, CML patients in chronic phase had reduced numbers of circulating myeloid and plasmacytoid DCs compared with healthy persons. 9,10 Contradictory data regarding the maturation status and function of BCR/ABLexpressing DCs have been published. BCR/ABL-expressing DCs had either a normal maturation status or lower expression of the costimulatory molecules CD80/CD83/CD40 compared with control DCs. 7,8,11,12 In acute myeloid leukemia, the plasmacytoid DCs were immature and could not elicit the proliferation of naive CD4 ϩ T cells. 13 Moreover, in vitro-generated BCR/ABL-expressing DCs have been reported to be defective in antigen processing. 7,11 In contrast, other studies suggested that BCR/ABL-expressing DCs are able to effectively stimulate the proliferation of allogeneic and autologous T cells. 8,14 Similarly, vaccination with autologous, nonirradiated leukemic DCs induced antileukemic T-cell responses in some CML patients. 15 The function of BCR/ABL-expressing DCs in vivo is unknown. Therefore, we analyzed the function of BCR/ABL-expressing DCs in a murine retroviral-induced bone marrow transduction and transplantation model. 16 To study antigen-specific immune responses, we used H8 transgenic...

CTL are induced by two pathways, i.e. direct priming, where tumor cells present tumor antigens to naïve specific CTL, and cross-priming, where professional APC cross-present captured tumor antigens to CTL. Here, we examined direct priming versus cross-priming after immunizing (H-2 b  H-2 d ) F1 mice with either H-2 b or H-2 d positive tumor cells transfected with the GP or nucleoprotein (NP) of lymphocytic choriomeningitis virus (LCMV). Cross-priming was observed for the immunodominant epitopes LCMV-gp33 andnp118, although direct induction resulted in higher CTL frequencies. In contrast, CTL specific for the subdominant epitopes LCMV-gp283 or -np396 were induced only if epitopes were presented directly on MHC class I molecules of the immunizing cell. The broader repertoire and the higher CTL frequencies induced after vaccination with haplotype-matched tumor cells resulted in more efficient anti-tumor and antiviral protection. Firstly, our results indicate that certain virus and tumor antigens may not be detected by CD8 1 T cells because of impaired cross-priming. Secondly, efficient cross-priming contributes to the immunodominant nature of a tumor-specific CTL epitope. Thirdly, vaccine strategies using autologous or syngenic antigen-expressing cells induce a broader repertoire of tumor-specific CTL and higher CTL frequencies.Key words: CD8 T cells . Cross presentation/priming . Tumor immunology IntroductionProfessional APC (pAPC) capture cells in the periphery, migrate to secondary lymphoid organs, cross-present the specific antigen and activate naïve CTL. Cross-priming enables the immune system to detect and respond to pathogens, tumors and tissue antigens that are exclusively expressed outside of secondary lymphoid organs. Cross-priming may be essential for the immunosurveillance of tumors, since most tumor cells lack costimulatory molecules and thus cannot efficiently stimulate protective anti-tumoral CTL immunity [1][2][3]. Alternatively, tumor cells directly present the internally synthesized tumor antigen via MHC class I molecules and activate naïve tumorspecific CTL [2,4]. This direct priming pathway requires that tumor cells reach secondary lymphoid organs. Different cellular pathways in the cross-presentation of exogenous antigen have been characterized. They can be separated into TAP-dependent and TAP-independent mechanisms [5,6]. Current literature favors the view that TAP-dependent mechanisms are dominating in vivo [6].Several studies have shown that stable cellular proteins in particulate form are the major source of cross-presented antigens in vivo, whereas soluble proteins, peptides, HSP-peptide complexes, RNA and DNA seem to play only a minor role in crosspresentation [7][8][9]. Although different cell types, including B cells, macrophages and endothelial cells, have been reported to have the capacity to cross-present antigens, CD81 DC are the predominant cell population capturing and cross-presenting tumor antigens 704 [10][11][12][13]. The maturation of DC and the efficiency of cross-priming c...